Recently, a new method based on a two compartment minimal model and deconvolution (Am. J. Physiol. 264: E829-E841, 1993; Comp. Meth. Prog. Biomed. 52: 147-156, 1997) has been proposed to estimate endogenous glucose production (EGP) from labeled IVGTT data. Our aim here is to compare this EGP profile with that independently obtained with the reference method, based on the tracer to tracee ratio (TTR) clamp. An insulin modified (0.03 U/kg body weight infused over 5 minutes) [6,6-2H2]glucose labeled IVGTT (0.33 g/kg of glucose) was performed in ten normal subjects. A second tracer ([U-13C]glucose) was also infused during the test in a variable fashion, so as to clamp endogenous glucose TTR. The TTR clamp was quite successful. As a result, the EGP profile reconstructed from [U-13C]glucose data with Steele's and with Radziuk's models were almost superimposable, thus confirming the substantial model-independence of the method. The deconvolution-obtained EGP profile, c alculated from [6,6-2H2]glucose data, showed remarkable agreement with that obtained from the TTR clamp. Some differences between the two profiles were noted in the estimated basal EGP and in the initial modalities of EGP inhibition. A high inter-individual variability was also observed with both methods in the resumption of EGP to baseline; variability was high both in the timing and the extent of resumption. In conclusion, the use of the two compartment minimal model of the IVGTT and deconvolution allows the estimation of a profile of EGP which is in very good agreement with that independently obtained with a TTR clamp.